Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

CRSwNP is a prevalent disease associated with major direct and indirect costs. Acute and
Chronic Rhinosinusitis are estimated to affect up to 16% of the US population. They account
for approximately 11 million or 1% of all office visits per year in the US and are the most
common cause for antibiotic prescriptions in the community. CRS alone impacts more than 30
million Americans resulting in $6.9 to $9.9 billion in annual healthcare expenditures and
$12.8 billion in productivity costs. The subset of patients in Europe with CRSwNP has been
estimated to be between 2 and 4.3% and is thought to be similar in the US. This population
remains one of the most challenging subgroups of CRS to manage effectively.

Recent evidence has focused on the sinonasal epithelial cell as a primary driver of the local
dysregulated immune response through secretion of type 2 helper T-cell(Th2) promoting
cytokines. While these studies suggest that epithelial cells are capable of orchestrating a
local immune response, the mechanisms responsible for regulating cytokine secretion are
poorly understood and may be influenced by the efflux function of epithelial
P-glycoprotein(P-gp). Studies by the investigator's group have demonstrated that P-gp is
overexpressed in the mucosa of patients with Th2 skewed CRS endotypes including CRSwNP and is
capable of regulating the secretion of Th2 polarizing cytokines. Together, these findings
suggest that P-gp participates in the non-canonical regulation of cytokine secretion within
CRSwNP and may thereby represent a druggable target.

The investigator's group therefore undertook a randomized, double-blind, placebo-controlled
trial to test the efficacy of low dose oral Verapamil HCl, a known first generation P-gp
inhibitor, for the treatment of CRSwNP. Our findings demonstrated significant efficacy in
both of the primary and secondary endpoints with no significant side effects. However, a
logistic regression analysis revealed two important relationships between baseline
characteristics and efficacy. First, patients with elevated BMI had significantly lower
improvements in the Sinonasal Outcome Test (SNOT-22) (p=0.01). The second is that patients
with the highest total mucus P-gp levels experienced less benefit(p=0.01).

While Verapamil HCl has significant potential for the treatment of CRSwNP through P-gp
inhibition, higher doses must be achieved to extend the effect to patients with elevated BMIs
and the highest levels of P-gp expression. As increasing oral dosing could result in cardiac
side effects, topical delivery represents a promising alternative. As exosome bound P-gp may
be more stable and representative of disease state than total mucus P-gp concentration,
exosomal P-gp demands further exploration as a novel biomarker of disease severity and drug
response.

Inclusion Criteria:

- Patients presenting to the Mass Eye and Ear Sinus Center

- Age 18-80 yrs old

- Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012
consensus criteria

- Post-operative with a Lund-Kennedy Poly score of <4

- Baseline SNOT-22 Score ≥ 30

Exclusion Criteria:

- Patients with the following comorbidities:

- GI Hypomotility

- Heart Failure

- Liver Failure

- Kidney Disease

- Muscular Dystrophy

- Pregnant or Nursing Females

- Steroid Dependency

- Hypertrophic Cardiomyopathy

- Any Atrial or Ventricular arrhythmia (ie. Atrial fibrillation, atrial flutter, etc..)

- Resting Heart Rate less than 60 beats per minute

- Baseline Systolic Blood Pressure less than 110 mmHg

- Baseline Diastolic Blood Pressure less than 70 mmHg

- Baseline Mean Arterial Pressure Less than 60 mmHg

- PR interval less than 0.12 seconds

- Patients taking the following medications:

- Aspirin

- Beta-blockers

- Cimetidine(Tagamet)

- Clarithromycin(Biaxin)

- Cyclosporin

- Digoxin

- Disopyramide(Norpace)

- Diuretics

- Erythromycin

- Flecainide

- HIV Protease Inhibitors(Indinavir, Nelfinavir, Ritonavir)

- Quinidine

- Lithium

- Pioglitazone

- Rifampin

- St Johns Wort

- Patients with cardiac or conduction abnormality picked up by screening EKG

- Post-op patients with surgery within 3 months prior to enrollment.